Derivatives of 9h-pyrido(3,4-b) indole and process of preparation

ABSTRACT

The preparation of derivatives of 1,2,3,4-tetrahydro-9H-pyrido (3,4-b) indole is described. In particular the preparation of acrylic esters of Beta -(3&#39;&#39;-hydroxypropyl)-1,2,3,4-tetrahydro9H-pyrido (3,4-b) indole is shown to proceed from the oxidation of a 2-alkyloxy-3-hydroxytetrahydropyran to its 2-alkyloxy-3oxotetrahydropyran derivative. The Wittig condensation is used to effect the reaction of this ketone with a phosphonoacetic ester giving rise to the carbalkoxy methylenic-substitution product, 2alkyloxy-3-(1&#39;&#39;-alkoxycarbonyl)methylidenetetrahydropyran. After acid hydrolysis of the 2-alkyloxy group, condensation is carried out with tryptamine resulting in the desired indole derivatives. Such compounds can be used in the facile preparation of alkaloids of the eburnamonie family.

United States Patent [191 Martel et al.

[ Jan. 21, 1975 [54] DERIVATIVES OF 9H-PYRIDO(3,4-B)

INDOLE AND PROCESS OF PREPARATION [75] Inventors: Jacques Martel, Bondy;Jean Buendia, Nogent-sur-Marne; Germain Costerousse, Vernouillet, all ofFrance [73] Assignee: Roussel Uclaf, Paris, France [22] Filed: July 24,1973 [21] Appl. No.: 382,061

[30] Foreign Application Priority Data July 31, 1972 France 72.27501[52] US. Cl.. 260/295 C, 260/326.l3 R, 260/345.8,

[51] Int. Cl C07d 27/54 [58] Field of Search 260/295 C [56] ReferencesCited UNITED STATES PATENTS 3,029,247 4/1962 Schut 260/296 PrimaryExaminer-G, Thomas Todd Attorney, Agent, or Firm-Bacon & Thomas [57]ABSTRACT The preparation of derivatives of l,2,3,4-tetrahydro- 9H-pyrid0[3,4-b] indole is described. In particular the preparation of acrylicesters of B-(3'- hydroxypropyl)-1,2,3,4-tetrahydr09H-pyrido [3,4-b]indole is shown to proceed from the oxidation of a 2-alkyloxy-3-hydroxytetrahydropyran to its 2-alkyloxy-3-oxotetrahydropyran derivative. The Wittig condensation is used toeffect the reaction of this ketone with a phosphonoacetic ester givingrise to the carbalkoxy methylenic-substitution product,2-alkyloxy-3-(l'- alkoxycarbonyl)methylidenetetrahydropyran. After acidhydrolysis of the 2-alkyloxy group, condensation is carried out withtryptamine resulting in the desired indole derivatives. Such compoundscan be used in the facile preparation of alkaloids of the eburnamoniefamily.

6 Claims, No Drawings DERIVATIVES OF )H-PYRIDOGA-B) INDOLE AND PROCESSOF PREPARATION This invention relates to derivatives of 9H-pyrido[3,4-b] indole and to a process for preparation of same.

An object of this invention is the provision of derivatives ofl,2,3,4tetrahyclro-9H-pyrido [3,4-b] indole of -w O H L O R Oxydation lWittig reaetionl C 0 O R L O R Hydrolysis l )0 H 0 (VII) N N II OII(VIII) oooa (I) The process comprises the reaction ofa 2-alkyloxy-3-hydroxy-tetrahydropyran of formula III in which R represents an alkylradical having from I to 4 carbon atoms with an oxidizing agent toobtain a 2-alkyloxy-3-ox0tetrahydropyran of formula IV:

LO/-ORI (IV) The compound of formula IV is treated, is the presence of abasic reagent, with a phosphorus derivative capable of substituting thecarbalkoxy-methylene group, i.e., CH-COOR, for the ketonic grouping anda derivative of tetrahydropyran of formula V1 is obtained:

COOR

L -o1r v vii Compound VII is condensed with tryptamine to obtain aderivative of indole of formula VIII:

II N/ (N /0 II (300R (\'Ill) This occurs by the cyclization in an acidmedium so as to form the derivative of l,2,3,4-tetrahydro-9H-pyrido[3,4-b] indole of general formula I.

This process has been found particularly advantageous for obtaining theproducts of formula I in a limited number of steps. This arises as aresult of the reactivity of compounds of formula VII with tryptamine,permitting the facile obtainment of the products of formula VIII. Thelatter compounds have a structure similar to that of the alkaloids ofthe eburanamonine family. The passage of products from formula I toeburnamonine is explained further on in the text.

In the process described above, different oxidizing agents can be usedto transform the trans 2-alkyloxy-3- hydroxytetrahydropyran into2-alkyloxy-3-oxotetrahydropyran. Preferably, the complex of chromicanhydride-pyridine is employed, but potassium permanganate, chromieanhydride or potassium bichromate can also be used.

The basic reagent in the presence of which the 2-alkyloxy-3-oxotetrahydropyran of formula IV is treated with thephosphorus derivative is preferably an alkaline amide, such as sodiumamide. However, tertiary organic bases such as triethylamine, oralkaline alcoholates such as sodium methylate, or sodium terbutylate orsodium teramylate or even alkaline hydrides such as sodium hydride canalso be used. The reaction which allows the compound of formula IV to betransformed into those of formula VI is known as the Wittig reaction. Itis brought about with the aid of a phosphorus derivative in a basicmedium. In this reaction a phosphonacetic ester of general formula V isused:

(IhOhIf-CI'HCOOR where R and R, which may be the same or different,represent an alkyl radical having from I or 4 carbon atoms; otherphosphorus derivatives can also be used, for example, thosecarbalkoxymethylenetriphenylphosphoranes of the general formula:

in which R represents an alkyl radical having from 1 to 4 carbon atoms.

The acid hydrolysis of the ether grouping of the compounds of formulaV], which allows their transformation into products of formula VII, canbe brought about with the help of aqueous mineral acids such as dilutehydrochloric acid, dilute sulfuric acid or paratoluene sulfonic acid indilute aqueous solution.

The cyclization of the indole derivatives of formula VIII intoderivatives of 9H-pyrido [3,4-b] indole of formula I can be effectedeither with the aid of an aqueous mineral acid. such as dilutehydrochloric acid or dilute sulfuric acid or with the aid of an organicaqueous acid, such as dilute acetic acid or dilute trifluoracetic acid,in an organic solvent miscible with water, such as an alcohol selectedfrom the group methanol, ethanol or isopropanol.

The invention also includes the application of products of formula I tothe preparation of products of formula ll:

in which R is the same as in formula I. This is accomplished by thereaction of a cyclizing agent on the compounds of formula I to obtainthe compounds of formula II. The preferred cyclization agent forobtaining the products of formula II is thionyl chloride, but numerousother agents can be used among which can be cited phosphorus trichlorideor tribromide and phosphorus pentachloride or pentabromide.

The products of formula II are intermediary products useful forobtaining medicinal substances or products necessary for the preparationof such substances. Thus, eburnamonine can be obtained by the reactionof ethylmagnesium halide in the presence of cuprous chloride oncompounds of formula II.

Belgian patent 776,337 has already described a preparation foreburnamonine beginning with an alkyl 5- halogenovalerate and tryptamineand having as an intermediate an alkyl l,2,3,4,6,7,12,12b(E)octahydroinodolo [2,3-a] quinolizidene acetate of formula II. It isknown that the alkaloids of the eburnamonine group are useful substancesfor human therapy due to their action on the circulation. (see forexample Therapeutic Chemistry,) 1971, page 137).

It is therefore useful to be able to completely synthetise eburnamonineby preparative conditions ofinterest to industry. The preparativetechniques already known for the synthesis of eburnamonine (see forexample J. Amer. Chem. Soc., 1960, 82 5941 and 1964, 86, 2946)necessitate the separation for stereoisomeres and have limited yields.They also do not permit production of the product on a large scalewithout difficulties.

The preparative process for compounds of formula II described herein andconsequent method for obtaining eburnamonine answer the preceedingdemands from the point of view of facility of production as well as fromthe point of view of economic returns. Moreover the introduction oftryptamine in the last stage avoids the necessity of purification ofcompounds of high molecular weight in the first stage and thusfacilitates the synthesis.

The process of the invention also provides new industrial produetsuseful notably as intermediates for the preparation of products offormula 1, namely the products of formula IV:

* L OR Stage A: 2-ethoxy-3-oxotetrahydropyran:

14.6 g. of trans-2-ethoxy-3-hydroxytetrahydropyran (prepared accordingto Bull. Soc. Chem., 1969, 621) are dissolved in a mixture of 500 cc ofether and 500 cc of benzene. 156 g of crystallized chromicanhydridepyridine complex (prepared according to Poos and Coll., J.Amer. Chem. Soc., 75, 422, 1953), are added 7 with agitation infractions of 26 g over a 5 hour period.

On completion of this addition the resulting mixture is agitated for onemore hour at room temperature. The solid residue is filtered and washedwith ether. This etheral extract is combined with the filtrate andwashed with a saturated sodium chloride solution.

After drying over sodium sulfate and evaporation in vacuum not exceeding30C., the residue is chromatographed on silica using a (9:1) mixture ofbenzene ethylacetate as eluent. Thus 10.3 g (72%) of2-ethoxy-3-oxotetrahydropyran are obtained in the form of colorless oil.

LR. Spectrum: C=O band at 1734 cm presence NMR Spectrum: Peaks at67.5-74.5 and 81.5 Hz (CH of the ethoxy); broad peaks at 200-250 Hz (CHof the ethoxy) peak at 275 Hz (2H).

Stage B: 2-ethoxy-3-(1'- ethoxycarbonyl)methylidenetetrahydropyran:

lg of sodium hydride is introduced as a 50% dispersion in mineral oilinto 50 cc of dimethoxyethane, recooled to 15C and a solution of 4.48 gof triethylphosphonoacetate (prepared according to the Beilsteindictionary 4,11,976) in 10 cc ofdimethoxyethane, is added in 30 minutesafter this addition the mixture is agitated for 30 minutes and recooledto between C and C. A solution of 2.9 g of2-ethoxy-3-oxotetrahydropyran, prepared in the preceeding stage,dissolved in cc of dimethoxyethane, is added and the reaction mixtureagitated for 30 minutes at 0C. cc of ice water are then added and theresulting mixure is poured into the water, extracted with methylenechloride and the extract washed again with water, dried and evaporated.

The residue is chromatographed on silica using a (9:1) mixture ofbenzene-ethylacetate as eluent. Thus 3,4 g (80%) of 2-ethoxy-3-(1'-ethoxycarbonyl)methylidenetetrahydropyran is obtained in the form ofcolorless oil.

l.R. Spectrum: C=O Band at 1713 cm; C=C Band at 1,658 cm presence of aC-OC Band.

NMR Spectrum: Peaks at 289 and 375Hz (2H); peaks at 338 and 345 Hz(ethylenic H). This NMR spectrum indicates that the product obtained isa mixture of E and Z isomers.

Stage C: 2-hydroxy-3-(1'- ethoxycarbonyl)methylidenetetrahydropyran:

2.52 of 2-ethoxy-3-(1'- ethoxycarbonyl)methlidenetetradhycleopyranprepared in the preceeding stage is dissolved in a mixture containing 24cc of dioxan, 2.4 cc of distilled water and 2.4 cc of 2N hydrochloricacid. It is agitated for 4 hours at room temperature. Sodium bicarbonateis added, then extracted with methylene chloride. After evaporating thesolvent in vacuum, the residue is dried. It is then chromatographed onsilica eluting with a (6:4) mixture of benzene-ethyl acetate. Thus 1.15g (52%) of 2-hydroxy 3-( 1 -ethoxycarbonyl)methylidenetetrahy' dropyranis obtained in the form of colorless oil.

I.R. Spectrum: C=C Band at 1,713 cm"; C=C band at 1,658 cm; OH band at3,585 cm.

NMR Spectrum: Peaks at 313 and 393 Hz (2H); peaks at 340 and 351 Hz(ethylenic H). This NMR spectrum indicates that the product obtained isa mixture of E and Z isomers.

Stage D: Ethyl 3-(3'-hydroxypropyl-4-[B-(3"-indolyl)ethylimino]-2-butenoate:

560 mg of tryptamine are dissolved in 20 cc of henzene with agitationunder a nitrogen atmosphere. 650 mg of 2-hydroxy-3-(1"ethoxycarbonyl)-methylidenetetrahydropyran dissolved in 15 cm of benzene are added. Thesolution is agitated for one hour at room temperature, then heated toreflux for 4 hours eliminating the water which has formed. The benzeneis then removed by evaporation and 1.2 g of ethyl 3-( 3-hydroxypropyl)-4-[B-( 3 indolyl)ethy1imino]- 2-butenoate is obtained inthe form of colorless oil. This product is used as it is for the rest ofthe synthesis.

l.R. Spectrum: C=O Band at 1,712 cm; NH Band at 3,476 cm; presence ofdouble bonds at 1.623 cm.

U.V. Spectrum: (ethanol):

k max. 221nm ($46650) kmax. 280nm (F6850) kmax 290nm (e=5800)lnflections at 240 and 272 nm.

Stage E: Ethyl B-(3-hydroxypropyl)-1,2,3,4- tetrahydro-9H-pyrido-[3,4-b]indole l-acrylate.

450 mg of ethyl 3-(3-hydroxyproply) 4[B-(3- indolyl)ethyliminolZ-butenoate obtained in the preceeding stage is dissolved in35 cc of ethanol. 1.8 cc of 6N hydrochloric acid are added dropwise andthe solution agitated for 2 hours at room temperature. After pouringinto water, the mixture is made alkaline with sodium hydroxide andextracted with methylene chloride. After washing with water and dryingover sodium sulfate it is evaporated in vacuum to dryness. The residueis chromatographed on silica and eluted with a (523:2) mixture ofchloroform-ethylacetate-ethanol. Thus 200 mg (40%) of ethyl,B-(3-hydroxypropyl)- l,2,3,4-tetrahydro-9H-pyrido [3,4-b] indolel-acrylate are obtained in the form of a friable foam. The productrecrystallized from ether has a melting point of -150C.

I.R. Spectrum: C=O Band at 1,710 cm ;C=C bands at 1,642 and 1,651 cm; NHband at 3,452 cm UiV. Spectrum (ethanol):

Amax. 224nm (e=3,8540) kmax; 277nm (e=7,020) emax. 282nm (F7,120) )tmax.292mm (s=7,160)

EXAMPLE 2 Ethyl 1,2,3,4,6,7,12,12b-(E)-octahydroindolo [2,3-

a]quinolizylidene acetate:

327 mg. of ethyl B-(3'-hydroxypropyl)-1,2,3,4-tetrahydro-9H-pyrido[3,4-b] indole-l-acrylate is suspended in 5 cc of benzene containing 0.2cc of pyridine. 0.1 cc of thionyl chloride is added dropwise and thesolution agitated for 1 hour at 20C under a nitrogen atmosphere. Thereaction solution is then poured into an aqueous solution of sodiumbicarbonate and extracted with methylene chloride. After washing withwater and drying over sodium sulfate, it is evaporated to dryness invacuum. The residue is chromatographed on silica and eluted with a(513:2) mixture of chloroform -ethylacetate-ethanol. Thus 121 mg (40%)of ethyl 1,2,3,4,6,7,12,12b-(E)-octahydroindolo [2,3-a] quinolizylidineacetate are obtained in the form ofa friable foam, which, aftercrystallization from ether, has a melting point of l58l60C.

I.R. Spectrum C=O Band at 1,709 cm C=C Band at 1,650 cm NH Band at 3,458cm"; deformation of C=C at 886 cm.

NMR Spectrum: triplet at 68.5-76 and 83 Hz (CI-I ofCO CI-I CH quadrupletat 240-247-254- and 261.5 Hz (-CI-I- ofCO CI-I -CH peak at 267 Hz (H atthe position 12 b); peak at 349 Hz (H of =CH-CO- FCHZCHQ) Preparation of(i) eburnamonine:

4.30 cc of ethylmagnesium bromide in 0.95 m/] tetra-. hydrofuran and 20mg of cuprous chloride are mixed' in a nitrogen atmosphere at 25C. Themixture is agitated for minutes and then recooled to 10C. A solution of412 mg of the product obtained according to example 2 in 4 cc oftetrahydrofuran are added over a minutes; After standing at 10C for 1hour and at 0C for 30 minutes the mixture is poured into an aqueoussolution of ammonium chloride and agitated. Then, the mixture isextracted with methylene chloride and the methylene chloride extract isdried over magnesium sulfate and the solvent evaporated. The residue ischromatographed on silica and eluted with a (6:311) mixture ofchloroformethylacetate-ethanol. 176 mg of product are obtained that ispurified by recrystallization from ethanol. After drying, 152 mg ofracemic eburnamonine are obtained, having a melting point of 204C.

What is claimed is: g

l. A derivative of 1,2,3,4-tetrahydro-9H-pyrido [3,4- b] indole of theformula;

NH O H COOR (I) in which R represents an alkyl radical having from 1 to4 carbon atoms.

2. Ethyl B-(3-hydroxypropyl)-l,2,3,4-tetrahydro- 9I-I-pyrido [3,4-b]indole l-acrylate.

3. A process for the preparation of a compound of the formula:

comprising reacting a tetrahydropyran of the formula:

mwon 111 in which R represents an alkyl radical having from 1 to 4carbon atoms with an oxidizing agent so as to obtain a2-alkoxy-3-oxo-tetrahydropyran of the formula:

* Lo/ o R m) in which R is the same as defined above, treating thecompound of formula IV in the presence of a basic reagent, with aphosphorus derivative capable of substituting a carbalkoxymethylenegrouping for the ketonic grouping to provide a derivative oftetrahydropyran of the formula:

condensing the compound of formula VII with tryptamine to obtain anindole derivative of the formula:

N /I I OH H V I (I O O R (VIII) and cyclizing the compound of formulaVIII in an acid medium to provide a derivative of 1,2,3,4-tetrahydro-9H-pyrido [3,4-b] indole of the formula I.

4. A process according to claim 3 in which the oxidizing agent whichreacts with the 2-alkyloxy-3-hydroxy tetrahydropyran of formula III is acomplex of chromic anhydride-pyridine.

5. A process according to claim 3 in which the basic reagent in whosepresence the phosphorus derivative reacts on the2-alkyloxy-3-oxotetrahydropyran of formula IV is sodium amide.

6. A process according to claim 3 in which the phosphorus derivativethat reacts on the product of formula IV, is a phosphonoacetic ester ofthe formula:

(lt1O)1PCIInG0OR v where R and R, which may be the same or different,represent an alkyl radical having from 1 to 4 carbon atoms.

1. A DERIVATIVE OF 1,2,3,4-TETRAHYDRO-9H-PYRIDO INDOLE OF THE FORMULA,2. Ethyl Beta -(3''-hydroxypropyl)-1,2,3,4-tetrahydro-9H-pyrido (3,4-b)indole 1-acrylate.
 3. A process for the preparation of a compound of theformula:
 4. A process according to claim 3 in which the oxidizing agentwhich reacts with the 2-alkyloxy-3-hydroxy tetrahydropyran of formulaIII is a complex of chromic anhydride-pyridine.
 5. A process accordingto claim 3 in which the basic reagent in whose presence the phosphorusderivative reacts on the 2-alkyloxy-3-oxotetrahydropyran of formula IVis sodium amide.
 6. A process according to claim 3 in which thephosphorus derivative that reacts on the product of formula IV, is aphosphonoacetic ester of the formula: